The central nervous system (CNS) remains an important frontier in the study of HIV disease, since the CNS is a potential reservoir of virus that is relatively inaccessible to anti-retroviral therapy, and since the mechanism of the development of HIV dementia is still not completely understood. In this program project application we propose to continue our studies of HIV dementia (HIVD) with projects that will be supported by cores. In one project. Dr. F. Gonzalez-Scarano will continue his studies of neurotropism using primary cultures of CNS cells, and specifically microglia, and map the determinants of fusion in microglial. In another project Dr. W. Kerr will use a SCID-hu mouse model to study trafficking of bone-marrow derived cells into the CNS, to determine the potential influence of HIV infection in this trafficking, and to begin in vivo studies on the pathophysiology and therapy of CNS disease. In another project, Dr. D. Kolson will develop new strategies for gene therapy of CNS cells, taking particular advantage of 'reverse pseudotypes' a system that he and collaborators developed recently, to kill HIV infected cells, and to develop neuroprotective approaches to therapy of HIVD. Still yet another project, which will be headed by Dr. R. Pomerantz, will study the effects of down-regulation of chemokine receptors on infection of CNS-derived cells, and on the induction of apoptosis. The last project, Drs. R. Collman and P. Crino will study the use of chemokine receptors in the regional compartmentalization of viral genotypes by amplification of proviral sequences from single cells in fixed brain from patients with HIVD. These projects will be supported by cores: (a) an administrative core that will be responsible for the overall conduct of the program, (b) a pathology core that will analyze the tissues from experimental animals and provide tissues to another project and (c) a cell culture core that will provide primary cell cultures to several projects. Together, the components of this program project will enhance our understanding of the virology and pathophysiology of HIVD, and provide novel therapeutic strategies for managing this complication.